Effects of phytoestrogens on sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Ca2+ uptake into cardiac sarcoplasmic reticulum

Phytoestrogens are naturally occurring estrogenic compounds found in plants and plant products. These compounds are also known to exert cellular effects independent of their interactions with estrogen receptors. We studied the effects of the phytoestrogens phloretin, phloridzin, genistein, and biochanin A on Ca2+ uptake into the cardiac muscle sarcoplasmic reticulum (SR). Genistein and biochanin A did not affect SR Ca2+ uptake. On the other hand, phloretin and phloridzin decreased the maximum velocity of SR Ca2+ uptake but did not affect the Hill coefficient or the Ca2+ sensitivity of uptake. Measurements of the ATPase activity of the cardiac SR Ca2+ pump (SERCA2a) revealed direct inhibitory effects of phloretin and phloridzin on SERCA2a. Neither compound induced a detectable change in the permeability of the SR membrane to Ca2+. These results indicate that phloretin and phloridzin inhibit cardiac SR Ca2+ uptake by directly inhibiting SERCA2a.